Abstract
Hsp70 chaperone is known to stimulate anti-tumour immunity in a variety of cancer models. Here we demonstrated that the addition of purified recombinant Hsp70 to the culture medium facilitated cancer cell cytolysis by lymphocytes. Importantly, exogenous Hsp70 triggered secretion of the intracellular Hsp70 to a cell surface and extracellular milieu, which played a role in cytolysis because down-regulation of the endogenous Hsp70 reduced both its presence at the cell surface and the lymphocyte-mediated cytolysis. Inhibitors that target both the ATPase and the peptide-binding domains of Hsp70 molecule potently decreased its anti-tumor effect. Using a variety of cell transport markers and inhibitors, we showed that the exchange of exogenous and intracellular Hsp70 is supported by classical and non-classical transport pathways, with a particular role of lipid rafts in the chaperone's intracellular transport. In conclusion, exogenous Hsp70 can eject endogenous Hsp70, thus exerting anticancer activity.
Highlights
Hsp70, play a dual role in cancer cells: the elevation of their content enhances cell protection to a variety of cytotoxic factors, while cells over-expressing Hsp70 have been shown to transport the chaperone to the surface which leads to their sensitization to specific and non-specific immune responses [1]
During 3 h of incubation with labelled exo-Hsp70, endogenous chaperone stained with SPA810 antibody appeared at the cell surface as bright green spots, and the number of such cells increased with time (Fig. 1A)
During last few years a few of newer anti-cancer techniques were reported targeting Hsp70 protective power in tumour cells. One of the latter is based on Hsp70 induction by heat stress and administration of bortezomib, inhibitor of proteasomes; their combined action was shown to provide the exclusively high apoptogenic effect suggesting that the protective role of the intracellular Hsp70 be surmounted [24]
Summary
Hsp, play a dual role in cancer cells: the elevation of their content enhances cell protection to a variety of cytotoxic factors, while cells over-expressing Hsp have been shown to transport the chaperone to the surface which leads to their sensitization to specific and non-specific immune responses [1]. The specific response of CD4- and/or CD8-positive cells to tumour can be triggered by Hsp released from dying or alive cancer cells [5,6]. Innate immunity can be triggered by the exogenous Hsp (exo-Hsp70), as proven in experiments where pure recombinant chaperone was shown to activate NF-kappaB factor system through TLR2/TLR4 [8,9]. Some effects of exogenous Hsp can be related to its recognition by Lox and SREC scavenger receptors or TLR2/TLR4 innate immune receptors [14]
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